Upper gastrointestinal (GI) cancer, including gastric cancer, esophageal cancer, and pancreatic cancer, is a prominent worldwide cause of malignant disease and mortality. Indeed, gastric cancer is one of the leading causes of cancer-related deaths worldwide, and is the leading cause of cancer-related deaths in Asia.
The pathway to gastric carcinogenesis is mediated through global changes in the lineages of the stomach. Studies over the past 15 years have demonstrated that the major primary cause of gastric cancer in humans is chronic infection with particular sub-classes of the bacterium, Helicobacter pylori. See Blaser, M., and Parsonnet, J. 1994. Parasitism by the bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia. J. Clin. Invest. 94:4-8; and Parsonnet, J, Friedman, G D, Vandersteen, D P, Chang, Y, Vogelman, J H, Orentreich, N, and Sibley, R K, 1991. Helicobacter pylori infection and the risk of gastric cancer, N Engl J Med 325:1127-31. Such findings prompted the World Health Organization to designate H. pylori as a Class I carcinogen.
Two factors contributing to the evolution of gastric cancer in the presence of chronic H. pylori infection are the following: (1) the infection elicits a prominent inflammatory response throughout the gastric mucosa; and (2) chronic infection leads to toss of glandular lineages in the gastric fundus, especially acid-secreting parietal cells and pepsin-secreting chief cells. Whether focal or global, oxyntic atrophy, or the loss of parietal cells, appears as a prerequisite for the development of gastric cancer. See El-Zimaity, H M T, Ota, H, Graham, D Y, Akamatsu, T, and Katsuyama, T, 2002. Patterns of gastric atrophy in intestinal type gastric carcinoma, Cancer 94: 1428-36.
The loss of parietal cells leads to emergence of metaplastic lineages within the gastric mucosa that are predisposed to neoplastic transformation. Following on oxyntic atrophy, subjects may show varying levels of foveolar hyperplasia. This increase in surface cell numbers is likely a reactive response to increases in gastrin release secondary to hypochlorhydria. Oxyntic atrophy also leads to mucous cell metaplasia. Studies over the last decade have increasingly emphasized the association of precedent mucous cell metaplasias with the development of upper gastrointestinal cancers in the esophagus, pancreas and stomach.
Development of esophageal cancer is closely linked with Barrett's epithelial metaplasia and pancreatic adenocarcinoma arises from discrete mucous cell metaplasias. See Biankin, A. V., Kench, J. G., Dijkman, F. P., Biankin, S. A., and Henshall, S. M. 2003. Molecular pathogenesis of precursor lesions of pancreatic ductal adenocarcinoma. Pathology 35:14-24; and Cameron, A. J., Lomboy, C. T., Pera, M., and Carpenter, H. A. 1995. Adenocarcinoma of the esophagogastric junction and Barrett's esophagus. Gastroenterology. 109:1541-1546.
While the association of cancer with cell atrophy and inflammation is now accepted, the intervening cellular events that mediate the progression from atrophy to neoplasia are not entirely clear. Also, while the association of upper GI-type cancers with chronic H. pylori infection and oxyntic atrophy is accepted, the connections between discrete metaplasias and cancer are less clear. Further studies may provide insight into these details.
With regard to mortality and morbidity associated with upper GI cancer, both have been lowered due to early diagnosis through screening. Rigorous upper endoscopic surveillance is currently considered to be the most effective screening method; however, the process is invasive, unpleasant, time-consuming, and costly. Accordingly, there remains a need in the art for an effective screening method to identify risk of upper GI cancer in subjects, which overcomes the drawbacks associated with currently-available screening methods.